Dyslipidemia, including high levels of low-density lipoprotein (LDL) cholesterol (LDL-C), is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of death and major health care costs worldwide. The association between LDL-C and the risk of ASCVD has been established over decades of genetic and biochemical studies, observational epidemiological and ecological studies, and in vitro and animal experiments. Lowering LDL-C reduces ASCVD events, demonstrating that LDL-C has a central, causal role in coronary heart disease (CHD) and ASCVD. Accordingly, fixed doses of cholesterol-lowering drugs are used as the primary approach for reducing ASCVD risk. In particular, elevated LDL-C is most frequently treated with statins (3-hydroxy-3-methylglutaryl-co-enzyme-A reductase inhibitors). Statins lower LDL-C up to 50% from baseline, and reduce ASCVD risk by 15-37%.
Yet, a residual 60-80% of ASCVD risk remains, which causes major vascular events in about 20% of patients with CHD, even under optimal statin treatment. Moreover, statins can cause muscle symptoms such as pain, tenderness, stiffness, cramping, weakness, fatigue, myopathy, and rhabdomyolysis. Further, although non-statin agents including bile acid-binding resins, fibrates, niacin, and ezetimibe significantly improve lipid profiles, none provides an additional risk reduction for cardiovascular events when combined with a statin. Accordingly, there is a need for improved non-statin drugs for lowering LDL-C levels and reducing the risk of ASCVD.